Particulate Matter and Incident Chronic Kidney Disease in Japan: The Ibaraki Prefectural Health Study (IPHS)

Introduction: Global health hazards caused by air pollution, such as chronic kidney disease (CKD), have been gaining attention; however, air pollution-associated CKD has not been explored in Japan. Methods: We examined 77,770 men and women with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 in the Ibaraki Prefecture who participated in annual community-based health checkups from 1993 at 40-75 years old and were followed up through December 2020. The outcome was newly developed kidney dysfunction with eGFR of <60 ml/min/1.73 m2 during follow-up. To assess air pollution, a PM2.5 exposure model was employed to estimate yearly means at 1 × 1-km resolution, converted into means at the municipal level. Hazard modeling was employed to examine PM2.5 concentrations in residential areas as a risk factor for outcomes. Results: Participants were distributed across 23 municipalities in the Ibaraki Prefecture, with PM2.5 concentrations between 16.2 and 33.4 μg/m3 (mean, 22.7 μg/m3) in 1987-1995 as the exposure period. There were 942 newly developed kidney dysfunctions during follow-up. Based on 1987-1995 PM2.5 concentrations as the baseline exposure, the multivariate-adjusted hazard ratio per 10-μg/m3 increase in PM2.5 for newly developed kidney dysfunction was 1.02 (95%CI, 0.80-1.24) in men and 1.19 (95%CI, 0.95-1.44) in women. Conclusions: Elevated PM2.5 did not represent a significant risk factor for incident CKD in a prefecture in Japan.


Introduction
Epidemiological studies on cardiovascular disease and ambient air concentrations of particulate matter with a diameter of ≤2.5 μm (PM 2.5 ), predominantly originating from combustion sources, have been carried out by numerous researchers since the 1990s and have provided a solid base of evidence (1), ( 2), (3), (4) .Considering the pathophysiology of cardio-renal syndrome, the involvement of PM 2.5 in chronic kidney disease (CKD) has recently been attracting attention (5), ( 6), (7) .Considering the links between air pollution and kidneys, experimental evidence has shown that exhaust particles might cause oxidative stress, endothelial dysfunction, and immune inflammation such as the production of tumor necrosis factor α, which leads to endothelial damage; in turn, progressive and cumulative kidney damage and an increased long-term risk of adenine-induced CKD mice model (8) .However, epidemiological studies on associations between exposure to PM 2.5 and the risk of CKD remain scant in contrast to studies on cardiovascular disease (9), (10), (11), (12) .Recently published results from systematic reviews and meta-analyses have indicated PM 2.5 as a risk factor for CKD (13), (14) .The publications selected to evaluate the risk of CKD based on PM 2.5 concentration were limited to those from the United States, Korea, and Taiwan, and stud-ies on links between PM 2.5 and CKD in Japan remain lacking.Since concentrations of PM 2.5 vary widely between different countries, different municipalities within a country, and even different areas within a municipality (5) , epidemiological studies on a country-by-country or region-by-region basis are thus important.This study therefore examined whether an association exists in Japan between PM 2.5 and the development of CKD from a longitudinal perspective study.

Study design and study population
This prospective observational cohort study is being carried out as part of the Ibaraki Prefectural Health Study (IPHS) (15), (16) .Ibaraki Prefecture is located adjacent to the Tokyo Metropolitan Area; it covers 6,097 km 2 (representing 1.6% of Japan's total land area), and it has a population of approximately 28 million people.The southern part of the prefecture is urban and within 1 hour's commuting distance of Tokyo, and the central and northern parts are rural and predominantly agricultural.Hence, the mean annual PM 2.5 concentration in the prefecture is high in the south and low in the north.Thirty-eight of the 85 municipalities that existed in the prefecture in 1993 were selected as target areas.Informed consent to conduct an epidemiological study based on guidelines of the Council for International Organizations of Medical Science was obtained from community representatives.We included 97,047 residents (33,133 men and 63,914 women) in Ibaraki Prefecture who participated in annual community-based health checkups beginning in 1993 at 40-75 years old.These health checkups were performed by local municipalities based on Japan's Health Service Law for the Aged.After excluding 2,254 cases with incomplete data and 17,023 cases with an estimated glomerular filtration rate (eGFR) of <60 ml/min/1.73m 2 at baseline, the number of final subjects was 77,770 (28,405 men and 49,365 women).This study was conducted according to the guidelines of the Declaration of Helsinki, and the original study protocol was approved by the ethics committee at Ibaraki Prefectural Office (approval no.R3-4) and then approved by the University of Tsukuba (#1628-1).

Exposure assessment
For this study, PM 2.5 concentration in 1993 was applied for the background exposure index.To assess air pollution, a national-scale PM 2.5 exposure model was utilized to estimate monthly means at a 1 × 1-km resolution across Japan for the period from 1987 to 2016 (17) .Briefly, a neural network model was developed using various predictors against the monitored PM 2.5 concentrations.The estimates were evaluated to be accurate with R 2 values greater than 0.73 through various validation approaches.Gridded PM 2.5 concentrations were averaged across the municipal level in each fiscal year.Individuals were assigned the average PM 2.5 exposure from 1987 to 1995 in the municipality of their residence in 1993.

Follow-up and outcomes
The participants were followed annually from the baseline in 1993 until the development of kidney dysfunction or the end of 2020.Maximum and median durations of follow-up were thus 27.7 and 22.5 years.Over the study period, the proportion of subjects lost to follow-up was 4.6%.Details regarding the methods applied for mortality surveillance have been reported previously (15), (16) .The outcome was newly developed kidney dysfunction with eGFR of <60 ml/min/1.73m 2 during follow-up.Serum creatinine was measured by the modified method of Jaffe's reaction using the automated analyzer (RX-30, Nihon Denshi Inc., Tokyo, Japan).The eGFR was calculated by using the abbreviated equation developed at Cleveland Clinic laboratory for the Modification of Diet in Renal Disease Study as follows: GFR (ml/min/1.73m 2 ) = 186.3× age −0.203 × serum creatinine level −1.154 × (0.742 if female) (18) .

Potential confounders
Potential confounding factors were basically selected according to our previous research analyzing cardiovascular deaths in IPHS (16) .However, the cohort does not have any information on social contexts that may influence the development of CKD.For example, other cohort studies have analyzed social factors, including educational levels, income, marital status, education, and occupation as covariates (9), ( 10), (11) .In this study, the selected factors in this study were age, sex, hypertension category (19) , antihypertensive treatment, cigarette smoking (never, past, occasional, and habitual smoker), abnormal glucose tolerance (hyperglycemia and/or diabetes treatment), alcohol intake (never, occasional, and habitual drink), body mass index, serum total cholesterol, high-density lipoprotein cholesterol, use of lipid-lowering drugs, and dipstick proteinuria in the baseline year.As background, the mean values and prevalence of these potential confounding factors were calculated (Table 1).

Statistical analysis
Hazard ratios (HRs) and 95% confidence intervals (95% CIs) of baseline difference in PM 2.5 concentration as a continuous value (per 10-μg/m 3 increase) for the outcomes were calculated with adjustment for age and other potential confounders using Cox proportional hazards modeling.As there were sex differences in previous studies regarding the risk of PM 2.5 for cardiovascular mortality in IPHS (16) , a sex stratification was also applied in the present analysis of the development of CKD.Because PM 2.5 concentrations declined over the course study period, we preliminary carried out a sensitivity analysis by PM 2.5 exposure in a single year from 1987 to 1995 of the municipal (data not shown), and exposure level of any single year showed no obvious differences in trends for CKD incident risk; then, we decided to assign the average PM 2.5 exposure level from 1987 to 1995.All statistical analyses were carried out using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Results
Table 1 lists the baseline characteristics of study subjects categorized by sex (men, 37%) and PM 2.5 concentration.Figure 1 shows the distribution of PM 2.5 during 1987-1995 in the 23 municipalities where study subjects resided in Ibaraki Prefecture, with PM 2.5 concentrations varying from 18.9 to 31.0 μg/m 3 (mean, 22.7 μg/m 3 ; standard deviation, 4.5 μg/m 3 ) in 1987 and from 18.2 to 32.3 μg/m 3 (mean, 23.1 μg/m 3 ; standard deviation, 4.0 μg/m 3 ) in 1995.A north-south gradient in the PM 2.5 level was shown.Although concentrations showed a decreasing trend from 1998 to 2015 in most municipalities (Figure 2), those for the exposure period (1987-1995) had remained largely consistent with mean levels remaining within 20.6-24.0 μg/m 3 .

Discussion
In this longitudinal prospective study of a Japanese community-dwelling population of a prefecture, we examined an associ- The original analytical methods and general results are described elsewhere (17) .We developed a national-scale PM2.5 exposure model for Japan using measurements recorded between 2014 and 2016 to estimate means at 1 × 1-km resolution for 1987 through 2015.The data were reconstructed to be suitable for The Ibaraki Prefectural Health.The original analytical methods and general results were described in the reference (17) .
ation between exposure to PM 2.5 and the onset of kidney dysfunction based on an eGFR of <60 ml/min/1.73m 2 during the follow-up.To the best of our knowledge, this represents the first cohort study in Japan to examine the association between air pollution, as any kind of pollutants, and the risk of incident CKD.
The current IPHS study with 77,770 participants has shown a nonsignificant association between CKD and PM 2.5 within the range of 18.9-31.0μg/m 3 in 1987.Although the association did not reach statistical significance in this study, environmental exposure to elevated concentrations of PM 2.5 may be a novel risk factor for the development of renal dysfunction, independent of classical CKD risks such as hypertension and diabetes, consistent with a recent systematic review (13) and two additional studies in the United States (11) and China (12) .In the United States, a large population of 2.4 million veterans, despite a low median exposure of 11.8 (interquartile range, 10.1-13.7)μg/m 3 across the whole country, showed that a 10μg/m 3 increase in PM 2.5 concentration was associated increased risk of eGFR of <60 ml/min/1.73m 2 (HR, 1.21; 95%CI, 1.14-1.29) (11).In a study from China, with a high and wide range of exposures, from 31.3 to 87.5 μg/m 3 across the whole country, an increase of 10 μg/m 3 in PM 2.5 was positively associated with CKD prevalence (odds ratio, 1.28; 95%CI, 1.22-1.35),from the data of about 47,000 people (12) .The smaller variation of PM 2.5 levels in this Japanese prefectural study compared to the Chinese study might be one reason why we did not detect the association.Presently, analyses of the association between CKD incidence and PM 2.5 are limited to the country level, but not international scale, and significant differences have been found in cases with large land areas, such as the United States (11) and China (12) , but not in cases Age-adjusted and multivariable-adjusted hazard ratio per 10-μg/m 3 increase in PM 2.5 exposure for incidence of eGFR of <60 ml/min/1.73m 2 during follow-up (A).The model was adjusted for sex, age, body mass index, blood pressure, total cholesterol, high-density lipoprotein cholesterol, glucose, treatment for diabetes, treatment for hypertension, treatment for hyperlipidemia, current smoking habit, drinking habit, and dipstick proteinuria at the baseline year of 1993.Exposure information for means of 1987-1995 was employed.HRs were also evaluated in men (B) and in women (C).23FA1006).The corresponding author is employed by the University of Tsukuba and Hitachi Ltd., but neither funder played any additional role in data collection or analysis, the decision to publish, or the preparation of the manuscript.

Figure 1 .
Figure 1.Ambient PM 2.5 concentration in the study regionWe previously developed a national-scale PM 2.5 exposure model for Japan using measurements recorded between 2014 and 2016 to estimate means at a resolution of 1 × 1 km for the years 1987-2015.Data were reconstructed for suitability for the Ibaraki Prefectural Health Study, presenting a heat map for 1987-1995 as the exposure period.The original analytical methods and general results are described elsewhere(17) .

Figure 2 .
Figure 2. Trends in PM2.5 concentrations in the cohort study area.We developed a national-scale PM2.5 exposure model for Japan using measurements recorded between 2014 and 2016 to estimate means at 1 × 1-km resolution for 1987 through 2015.The data were reconstructed to be suitable for The Ibaraki Prefectural Health.The original analytical methods and general results were described in the reference(17) .

Figure 3 .
Figure 3. Hazard ratio of PM 2.5 concentration for newly developed kidney dysfunction.Age-adjusted and multivariable-adjusted hazard ratio per 10-μg/m 3 increase in PM 2.5 exposure for incidence of eGFR of <60 ml/min/1.73m 2 during follow-up (A).The model was adjusted for sex, age, body mass index, blood pressure, total cholesterol, high-density lipoprotein cholesterol, glucose, treatment for diabetes, treatment for hypertension, treatment for hyperlipidemia, current smoking habit, drinking habit, and dipstick proteinuria at the baseline year of 1993.Exposure information for means of 1987-1995 was employed.HRs were also evaluated in men (B) and in women (C).